8G0H

Human PARP1 deltaV687-E688 bound to UKTT5 (compound 10) and to a DNA double strand break.

Summary for 8G0H

• Entry DOI: 10.2210/pdb8g0h/pdb
• Related: 8FYY 8FYZ 8FZ1
• Descriptor: DNA (5'-D(*CP*GP*AP*CP*G)-3'), DNA (5'-D(*CP*GP*TP*CP*G)-3'), Poly [ADP-ribose] polymerase 1, ... (6 entities in total)
• Functional Keywords: parp, adp-ribose transferase, dna break detection, zinc finger, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 183458.13

Authors

Rouleau-Turcotte, E.,Pascal, J.M. (deposition date: 2023-01-31, release date: 2024-02-07, Last modification date: 2024-03-27)

Primary citation

Velagapudi, U.K.,Rouleau-Turcotte, E.,Billur, R.,Shao, X.,Patil, M.,Black, B.E.,Pascal, J.M.,Talele, T.T.
Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks.
Biochem.J., 481:437-460, 2024

PubMed Abstract: Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.

PubMed: 38372302
DOI: 10.1042/BCJ20230406

Experimental method

X-RAY DIFFRACTION (3.8 Å)